Statins have both cholesterol lowering and anti-inflammatory activities, whether mechanisms underlying their activities are independent remains unclear. The ATP-gated P2X4 receptor is a pro-inflammatory mediator. Here, we investigate the action of fluvastatin and other cholesterol depleting agents on native and recombinant human P2X4 receptor. Fluvastatin and mβCD suppressed P2X4-dependent calcium influx in THP-1 monocytes, without affecting P2Y receptor responses. mβCD or filipin III suppressed the current density of recombinant human P2X4 receptors. Human P2X2 was insensitive to cholesterol depletion. Cholesterol depletion had no effect on intrinsic P2X4 receptor properties as judged by ATP concentration–response relationship, receptor rundown or current decay during agonist occupancy. These data suggest fluvastatin suppresses P2X4 activity in monocytes through cholesterol depletion and not by modulating intrinsic channel properties.